Identification of a dual FLT3 and MNK2 inhibitor for acute myeloid leukemia treatment using a structure-based virtual screening approach

Shih-Chung Yen; Liang-Chieh Chen; Han-Li Huang; Wei-Chun HuangFu; Yi-Ying Chen; Tony Eight Lin; Ssu-Ting Lien; Hui-Ju Tseng; Tzu-Ying Sung; Jui-Hua Hsieh; Wei-Jan Huang; Shiow-Lin Pan; Kai-Cheng Hsu

doi:10.1016/j.bioorg.2022.105675

Identification of a dual FLT3 and MNK2 inhibitor for acute myeloid leukemia treatment using a structure-based virtual screening approach

Bioorg Chem. 2022 Apr:121:105675. doi: 10.1016/j.bioorg.2022.105675. Epub 2022 Feb 11.

Authors

Shih-Chung Yen¹, Liang-Chieh Chen², Han-Li Huang³, Wei-Chun HuangFu⁴, Yi-Ying Chen⁵, Tony Eight Lin⁶, Ssu-Ting Lien⁷, Hui-Ju Tseng⁸, Tzu-Ying Sung⁹, Jui-Hua Hsieh¹⁰, Wei-Jan Huang¹¹, Shiow-Lin Pan¹², Kai-Cheng Hsu¹³

Affiliations

¹ Warshel Institute for Computational Biology, The Chinese University of Hong Kong (Shenzhen), Shenzhen, Guangdong, People's Republic of China.
² Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan; Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, United States.
³ Ph.D. Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, Taipei, Taiwan; TMU Research Center of Drug Discovery, Taipei Medical University, Taipei, Taiwan; TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei, Taiwan.
⁴ Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan; Ph.D. Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, Taipei, Taiwan; TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei, Taiwan; Ph.D. Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
⁵ Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan; Biomedical Translation Research Center, Academia Sinica, Taipei, Taiwan.
⁶ Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan; Master Program in Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
⁷ Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
⁸ Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, United States.
⁹ Biomedical Translation Research Center, Academia Sinica, Taipei, Taiwan.
¹⁰ Division of the National Toxicology Program, National Institute of Environmental Health Sciences, National Institutes of Health, Durham, NC, United States.
¹¹ Ph.D. Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, Taipei, Taiwan; Graduate Institute of Pharmacognosy, College of Pharmacy, Taipei Medical University, Taipei, Taiwan; Ph.D. Program in Clinical Drug Development of Herbal Medicine, College of Pharmacy, Taipei, Taiwan; School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei, Taiwan.
¹² Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan; Ph.D. Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, Taipei, Taiwan; TMU Research Center of Drug Discovery, Taipei Medical University, Taipei, Taiwan; TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei, Taiwan; Ph.D. Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
¹³ Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan; Ph.D. Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, Taipei, Taiwan; TMU Research Center of Drug Discovery, Taipei Medical University, Taipei, Taiwan; TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei, Taiwan; Ph.D. Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan; Cancer Center, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan. Electronic address: piki@tmu.edu.tw.

PMID: 35182882
DOI: 10.1016/j.bioorg.2022.105675

Abstract

Fms-like tyrosine kinase 3 (FLT3) is considered a promising therapeutic target for acute myeloid leukemia (AML) in the clinical. However, monotherapy with FLT3 inhibitor is usually accompanied by drug resistance. Dual inhibitors might be therapeutically beneficial to patients with AML due to their ability to overcome drug resistance. Mitogen-activated protein kinase (MAPK)-interacting kinases (MNKs) phosphorylate eukaryotic translation initiation factor 4E (eIF4E), which brings together the RAS/RAF/ERK and PI3K/AKT/mTOR oncogenic pathways. Therefore, dual inhibition of FLT3 and MNK2 might have an additive effect against AML. Herein, a structure-based virtual screening approach was performed to identify dual inhibitors of FLT3 and MNK2 from the ChemDiv database. Compound K783-0308 was identified as a dual inhibitor of FLT3 and MNK2 with IC₅₀ values of 680 and 406 nM, respectively. In addition, the compound showed selectivity for both FLT3 and MNK2 in a panel of 82 kinases. The structure-activity relationship analysis and common interactions revealed interactions between K783-0308 analogs and FLT3 and MNK2. Furthermore, K783-0308 inhibited MV-4-11 and MOLM-13 AML cell growth and induced G0/G1 cell cycle arrest. Taken together, the dual inhibitor K783-0308 showed promising results and can be potentially optimized as a lead compound for AML treatment.

Keywords: Acute myeloid leukemia; Dual inhibitors; FLT3 inhibitors; MNK2 inhibitors; Structure-based virtual screening.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Apoptosis
Cell Line, Tumor
Cell Proliferation
Humans
Intracellular Signaling Peptides and Proteins
Leukemia, Myeloid, Acute* / drug therapy
Mutation
Phosphatidylinositol 3-Kinases
Protein Kinase Inhibitors / pharmacology
Protein Kinase Inhibitors / therapeutic use
Protein Serine-Threonine Kinases
fms-Like Tyrosine Kinase 3*

Substances

Intracellular Signaling Peptides and Proteins
Protein Kinase Inhibitors
FLT3 protein, human
fms-Like Tyrosine Kinase 3
MKNK2 protein, human
Protein Serine-Threonine Kinases